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| Item Type: | Article |
|---|---|
| Title: | R-loops trigger the release of cytoplasmic ssDNAs leading to chronic inflammation upon DNA damage |
| Creators Name: | Chatzidoukaki, O. and Stratigi, K. and Goulielmaki, E. and Niotis, G. and Akalestou-Clocher, A. and Gkirtzimanaki, K. and Zafeiropoulos, A. and Altmüller, J. and Topalis, P. and Garinis, G.A. |
| Abstract: | How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1(−/−) pancreatic cells. Treatment of Ercc1(−/−) animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1(−/−) paving the way for novel rationalized intervention strategies against age-related chronic inflammation. |
| Keywords: | Cytoplasm, DNA Damage, DNA Repair, Single-Stranded DNA, DNA-Binding Proteins, Endonucleases, Inflammation, R-Loop Structures, Animals, Mice |
| Source: | Science Advances |
| ISSN: | 2375-2548 |
| Publisher: | American Association for the Advancement of Science |
| Volume: | 7 |
| Number: | 47 |
| Page Range: | eabj5769 |
| Date: | 19 November 2021 |
| Official Publication: | https://doi.org/10.1126/sciadv.abj5769 |
| PubMed: | View item in PubMed |
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